HU183103B - Process for producing amino-alkoxy-pyrrolidin-2-ones - Google Patents
Process for producing amino-alkoxy-pyrrolidin-2-ones Download PDFInfo
- Publication number
- HU183103B HU183103B HU79SCHE685A HUSC000685A HU183103B HU 183103 B HU183103 B HU 183103B HU 79SCHE685 A HU79SCHE685 A HU 79SCHE685A HU SC000685 A HUSC000685 A HU SC000685A HU 183103 B HU183103 B HU 183103B
- Authority
- HU
- Hungary
- Prior art keywords
- pyrrolidone
- phenyl
- methoxy
- methoxyphenyl
- august
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 34
- -1 cyclic secondary amine Chemical class 0.000 claims description 30
- 238000002360 preparation method Methods 0.000 claims description 25
- 239000007858 starting material Substances 0.000 claims description 25
- YZTJYBJCZXZGCT-UHFFFAOYSA-N phenylpiperazine Chemical compound C1CNCCN1C1=CC=CC=C1 YZTJYBJCZXZGCT-UHFFFAOYSA-N 0.000 claims description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 20
- 150000001875 compounds Chemical class 0.000 claims description 17
- 229910052739 hydrogen Inorganic materials 0.000 claims description 13
- 239000001257 hydrogen Substances 0.000 claims description 13
- YJKFWWHTIYVILF-UHFFFAOYSA-N 4-[4-methoxy-3-(oxiran-2-ylmethoxy)phenyl]pyrrolidin-2-one Chemical compound COC1=CC=C(C2CC(=O)NC2)C=C1OCC1CO1 YJKFWWHTIYVILF-UHFFFAOYSA-N 0.000 claims description 11
- 150000002431 hydrogen Chemical class 0.000 claims description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 6
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- 238000009833 condensation Methods 0.000 claims description 6
- 230000005494 condensation Effects 0.000 claims description 6
- 150000002118 epoxides Chemical group 0.000 claims description 6
- 239000012442 inert solvent Substances 0.000 claims description 6
- IRGJLQOKVFMQEK-UHFFFAOYSA-N 4-[3-(3-chloropropoxy)-4-methoxyphenyl]pyrrolidin-2-one Chemical compound C1=C(OCCCCl)C(OC)=CC=C1C1CC(=O)NC1 IRGJLQOKVFMQEK-UHFFFAOYSA-N 0.000 claims description 5
- GNINXEFWQMKYJQ-UHFFFAOYSA-N 4-[3-[2-hydroxy-3-(4-phenylpiperazin-1-yl)propoxy]-4-methoxyphenyl]pyrrolidin-2-one Chemical compound COC1=CC=C(C2CC(=O)NC2)C=C1OCC(O)CN(CC1)CCN1C1=CC=CC=C1 GNINXEFWQMKYJQ-UHFFFAOYSA-N 0.000 claims description 5
- 150000001412 amines Chemical class 0.000 claims description 5
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- JJARDAHEBYRVPF-UHFFFAOYSA-N 4-[3-(2-chloroethoxy)-4-methoxyphenyl]pyrrolidin-2-one Chemical compound C1=C(OCCCl)C(OC)=CC=C1C1CC(=O)NC1 JJARDAHEBYRVPF-UHFFFAOYSA-N 0.000 claims description 3
- DRPQWQHQUSAZOL-UHFFFAOYSA-N 4-[3-(3-bromobutoxy)-4-methoxyphenyl]pyrrolidin-2-one Chemical compound C1=C(OCCC(C)Br)C(OC)=CC=C1C1CC(=O)NC1 DRPQWQHQUSAZOL-UHFFFAOYSA-N 0.000 claims description 3
- GQKJHQNCJIQOMT-UHFFFAOYSA-N 4-[3-(4-bromobutoxy)-4-methoxyphenyl]pyrrolidin-2-one Chemical compound C1=C(OCCCCBr)C(OC)=CC=C1C1CC(=O)NC1 GQKJHQNCJIQOMT-UHFFFAOYSA-N 0.000 claims description 3
- NDJGOUYSNKCBDK-UHFFFAOYSA-N 4-[3-(oxiran-2-ylmethoxy)phenyl]pyrrolidin-2-one Chemical compound C1NC(=O)CC1C1=CC=CC(OCC2OC2)=C1 NDJGOUYSNKCBDK-UHFFFAOYSA-N 0.000 claims description 3
- KOHVZXWSIIYGPZ-UHFFFAOYSA-N 4-[3-[3-hydroxy-4-(4-phenylpiperazin-1-yl)butan-2-yl]oxy-4-methoxyphenyl]pyrrolidin-2-one Chemical compound COC1=CC=C(C2CC(=O)NC2)C=C1OC(C)C(O)CN(CC1)CCN1C1=CC=CC=C1 KOHVZXWSIIYGPZ-UHFFFAOYSA-N 0.000 claims description 3
- YVUHVEYFRZMTOG-UHFFFAOYSA-N 4-[4-methoxy-3-[3-(4-phenylpiperazin-1-yl)butoxy]phenyl]pyrrolidin-2-one Chemical compound COC1=CC=C(C2CC(=O)NC2)C=C1OCCC(C)N(CC1)CCN1C1=CC=CC=C1 YVUHVEYFRZMTOG-UHFFFAOYSA-N 0.000 claims description 3
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 3
- UTBULQCHEUWJNV-UHFFFAOYSA-N 4-phenylpiperidine Chemical compound C1CNCCC1C1=CC=CC=C1 UTBULQCHEUWJNV-UHFFFAOYSA-N 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical group 0.000 claims description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- ABERUOJGWHYBJL-UHFFFAOYSA-N (4-fluorophenyl)-piperidin-4-ylmethanone Chemical compound C1=CC(F)=CC=C1C(=O)C1CCNCC1 ABERUOJGWHYBJL-UHFFFAOYSA-N 0.000 claims description 2
- JMVIVASFFKKFQK-UHFFFAOYSA-N 1-phenylpyrrolidin-2-one Chemical class O=C1CCCN1C1=CC=CC=C1 JMVIVASFFKKFQK-UHFFFAOYSA-N 0.000 claims description 2
- HCQBSGWAZMPLNH-UHFFFAOYSA-N 4-[3-methoxy-4-(oxiran-2-ylmethoxy)phenyl]pyrrolidin-2-one Chemical compound COC1=CC(C2CC(=O)NC2)=CC=C1OCC1CO1 HCQBSGWAZMPLNH-UHFFFAOYSA-N 0.000 claims description 2
- TYBIHQONGDOQJH-UHFFFAOYSA-N 4-[4-[2-hydroxy-3-(4-phenylpiperazin-1-yl)propoxy]-3-methoxyphenyl]pyrrolidin-2-one Chemical compound COC1=CC(C2CC(=O)NC2)=CC=C1OCC(O)CN(CC1)CCN1C1=CC=CC=C1 TYBIHQONGDOQJH-UHFFFAOYSA-N 0.000 claims description 2
- LJIYALDEFRXWMW-UHFFFAOYSA-N 4-[4-methoxy-3-[2-(4-phenylpiperazin-1-yl)ethoxy]phenyl]pyrrolidin-2-one Chemical compound COC1=CC=C(C2CC(=O)NC2)C=C1OCCN(CC1)CCN1C1=CC=CC=C1 LJIYALDEFRXWMW-UHFFFAOYSA-N 0.000 claims description 2
- NXJMCLYZLHVIPT-UHFFFAOYSA-N 4-[4-methoxy-3-[3-(4-phenylpiperazin-1-yl)propoxy]phenyl]pyrrolidin-2-one Chemical compound COC1=CC=C(C2CC(=O)NC2)C=C1OCCCN(CC1)CCN1C1=CC=CC=C1 NXJMCLYZLHVIPT-UHFFFAOYSA-N 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 239000000969 carrier Substances 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- JDYWZVJXSMADHP-UHFFFAOYSA-N lidanserin Chemical compound COC1=CC=C(C2CC(=O)NC2)C=C1OCCCN(CC1)CCC1C(=O)C1=CC=C(F)C=C1 JDYWZVJXSMADHP-UHFFFAOYSA-N 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims 2
- VNZLQLYBRIOLFZ-UHFFFAOYSA-N 1-(2-methoxyphenyl)piperazine Chemical compound COC1=CC=CC=C1N1CCNCC1 VNZLQLYBRIOLFZ-UHFFFAOYSA-N 0.000 claims 1
- VHFVKMTVMIZMIK-UHFFFAOYSA-N 1-(3-chlorophenyl)piperazine Chemical compound ClC1=CC=CC(N2CCNCC2)=C1 VHFVKMTVMIZMIK-UHFFFAOYSA-N 0.000 claims 1
- ZAFJOTXTPDUNER-UHFFFAOYSA-N 3-[3-[2-hydroxy-3-(4-phenylpiperazin-1-yl)propoxy]-4-methoxyphenyl]pyrrolidin-2-one Chemical compound COC1=CC=C(C2C(NCC2)=O)C=C1OCC(O)CN(CC1)CCN1C1=CC=CC=C1 ZAFJOTXTPDUNER-UHFFFAOYSA-N 0.000 claims 1
- GCMGNZAYELXVSK-UHFFFAOYSA-N 4-[3-(2-hydroxy-3-morpholin-4-ylpropoxy)-4-methoxyphenyl]pyrrolidin-2-one Chemical compound COC1=CC=C(C2CC(=O)NC2)C=C1OCC(O)CN1CCOCC1 GCMGNZAYELXVSK-UHFFFAOYSA-N 0.000 claims 1
- RHYLWLACLFGJQE-UHFFFAOYSA-N 4-[3-(2-hydroxy-3-piperidin-1-ylpropoxy)-4-methoxyphenyl]pyrrolidin-2-one Chemical compound COC1=CC=C(C2CC(=O)NC2)C=C1OCC(O)CN1CCCCC1 RHYLWLACLFGJQE-UHFFFAOYSA-N 0.000 claims 1
- BIFBFDVTKUZVDZ-UHFFFAOYSA-N 4-[3-[2-hydroxy-3-(4-phenylpiperazin-1-yl)propoxy]-4-methoxyphenyl]pyrrolidin-2-one;dihydrochloride Chemical compound Cl.Cl.COC1=CC=C(C2CC(=O)NC2)C=C1OCC(O)CN(CC1)CCN1C1=CC=CC=C1 BIFBFDVTKUZVDZ-UHFFFAOYSA-N 0.000 claims 1
- RMKVUOWDKCRZAH-UHFFFAOYSA-N 4-[3-[2-hydroxy-3-(4-pyridin-2-ylpiperazin-1-yl)propoxy]-4-methoxyphenyl]pyrrolidin-2-one Chemical compound COC1=CC=C(C2CC(=O)NC2)C=C1OCC(O)CN(CC1)CCN1C1=CC=CC=N1 RMKVUOWDKCRZAH-UHFFFAOYSA-N 0.000 claims 1
- WVKORPAQMQGSPN-UHFFFAOYSA-N 4-[3-[2-hydroxy-3-[4-(2-methoxyphenyl)piperazin-1-yl]propoxy]-4-methoxyphenyl]pyrrolidin-2-one Chemical compound COC1=CC=C(C2CC(=O)NC2)C=C1OCC(O)CN(CC1)CCN1C1=CC=CC=C1OC WVKORPAQMQGSPN-UHFFFAOYSA-N 0.000 claims 1
- ZFOSIXQWENCFAA-UHFFFAOYSA-N 4-[3-[3-[4-(3-chlorophenyl)piperazin-1-yl]-2-hydroxypropoxy]-4-methoxyphenyl]pyrrolidin-2-one Chemical compound COC1=CC=C(C2CC(=O)NC2)C=C1OCC(O)CN(CC1)CCN1C1=CC=CC(Cl)=C1 ZFOSIXQWENCFAA-UHFFFAOYSA-N 0.000 claims 1
- RQZZBZFNUMEROV-UHFFFAOYSA-N 4-[3-[3-[4-(4-fluorobenzoyl)piperidin-1-yl]-2-hydroxypropoxy]-4-methoxyphenyl]pyrrolidin-2-one Chemical compound COC1=CC=C(C2CC(=O)NC2)C=C1OCC(O)CN(CC1)CCC1C(=O)C1=CC=C(F)C=C1 RQZZBZFNUMEROV-UHFFFAOYSA-N 0.000 claims 1
- DSURIFVHTQWVMR-UHFFFAOYSA-N 4-[3-[3-[4-(furan-2-carbonyl)piperazin-1-yl]-2-hydroxypropoxy]-4-methoxyphenyl]pyrrolidin-2-one Chemical compound COC1=CC=C(C2CC(=O)NC2)C=C1OCC(O)CN(CC1)CCN1C(=O)C1=CC=CO1 DSURIFVHTQWVMR-UHFFFAOYSA-N 0.000 claims 1
- OFQLLOQNZARNAI-UHFFFAOYSA-N 4-[4-methoxy-3-[2-(4-phenylpiperazin-1-yl)ethoxy]phenyl]pyrrolidin-2-one;dihydrochloride Chemical compound Cl.Cl.COC1=CC=C(C2CC(=O)NC2)C=C1OCCN(CC1)CCN1C1=CC=CC=C1 OFQLLOQNZARNAI-UHFFFAOYSA-N 0.000 claims 1
- RKYLLWPCRSUXAP-UHFFFAOYSA-N 4-[4-methoxy-3-[4-(4-phenylpiperazin-1-yl)butoxy]phenyl]pyrrolidin-2-one Chemical compound COC1=CC=C(C2CC(=O)NC2)C=C1OCCCCN(CC1)CCN1C1=CC=CC=C1 RKYLLWPCRSUXAP-UHFFFAOYSA-N 0.000 claims 1
- CHOTZKKBDZLSFB-UHFFFAOYSA-N 5-[3-[2-hydroxy-3-(4-phenylpiperazin-1-yl)propoxy]-4-methoxyphenyl]pyrrolidin-2-one Chemical compound COC1=CC=C(C2NC(=O)CC2)C=C1OCC(O)CN(CC1)CCN1C1=CC=CC=C1 CHOTZKKBDZLSFB-UHFFFAOYSA-N 0.000 claims 1
- 239000004593 Epoxy Substances 0.000 claims 1
- 125000004122 cyclic group Chemical group 0.000 claims 1
- 239000003814 drug Substances 0.000 claims 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims 1
- SADPINFEWFPMEA-UHFFFAOYSA-N furan-2-yl(piperazin-1-yl)methanone Chemical compound C=1C=COC=1C(=O)N1CCNCC1 SADPINFEWFPMEA-UHFFFAOYSA-N 0.000 claims 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims 1
- GZRKXKUVVPSREJ-UHFFFAOYSA-N pyridinylpiperazine Chemical compound C1CNCCN1C1=CC=CC=N1 GZRKXKUVVPSREJ-UHFFFAOYSA-N 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 54
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 49
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 31
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 30
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 11
- 238000006243 chemical reaction Methods 0.000 description 11
- 239000012312 sodium hydride Substances 0.000 description 11
- 229910000104 sodium hydride Inorganic materials 0.000 description 11
- 239000002904 solvent Substances 0.000 description 10
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- 238000002844 melting Methods 0.000 description 5
- 230000008018 melting Effects 0.000 description 5
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- IBYHHJPAARCAIE-UHFFFAOYSA-N 1-bromo-2-chloroethane Chemical compound ClCCBr IBYHHJPAARCAIE-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 150000003335 secondary amines Chemical class 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 150000001340 alkali metals Chemical class 0.000 description 3
- 230000003276 anti-hypertensive effect Effects 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- LQYCTMPQLBCTQW-UHFFFAOYSA-N 4-[4-methoxy-3-[1-(oxiran-2-yl)ethoxy]phenyl]pyrrolidin-2-one Chemical compound COC1=CC=C(C2CC(=O)NC2)C=C1OC(C)C1CO1 LQYCTMPQLBCTQW-UHFFFAOYSA-N 0.000 description 2
- PUOQWRPUJCLVSX-UHFFFAOYSA-N 5-[4-methoxy-3-(oxiran-2-ylmethoxy)phenyl]pyrrolidin-2-one Chemical compound COC1=CC=C(C2NC(=O)CC2)C=C1OCC1CO1 PUOQWRPUJCLVSX-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 150000002989 phenols Chemical class 0.000 description 2
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Inorganic materials [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 2
- SSOLNOMRVKKSON-UHFFFAOYSA-N proguanil Chemical compound CC(C)\N=C(/N)N=C(N)NC1=CC=C(Cl)C=C1 SSOLNOMRVKKSON-UHFFFAOYSA-N 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Substances C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- 229940124549 vasodilator Drugs 0.000 description 2
- 239000003071 vasodilator agent Substances 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- ULTHEAFYOOPTTB-UHFFFAOYSA-N 1,4-dibromobutane Chemical compound BrCCCCBr ULTHEAFYOOPTTB-UHFFFAOYSA-N 0.000 description 1
- VWOJSRICSKDKAW-UHFFFAOYSA-N 1-(4-nitrophenyl)piperazine Chemical compound C1=CC([N+](=O)[O-])=CC=C1N1CCNCC1 VWOJSRICSKDKAW-UHFFFAOYSA-N 0.000 description 1
- YXGBQJQAKULVEL-UHFFFAOYSA-N 2-(1-bromoethyl)oxirane Chemical compound CC(Br)C1CO1 YXGBQJQAKULVEL-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- WTNOUZFUFCJWSB-UHFFFAOYSA-N 3-[4-methoxy-3-(oxiran-2-ylmethoxy)phenyl]pyrrolidin-2-one Chemical compound COC1=CC=C(C2C(NCC2)=O)C=C1OCC1CO1 WTNOUZFUFCJWSB-UHFFFAOYSA-N 0.000 description 1
- PAIFAXUSHBVXHY-UHFFFAOYSA-N 4-(3-hydroxy-4-methoxyphenyl)pyrrolidin-2-one Chemical compound C1=C(O)C(OC)=CC=C1C1CC(=O)NC1 PAIFAXUSHBVXHY-UHFFFAOYSA-N 0.000 description 1
- DOSDNEYPPVONJR-UHFFFAOYSA-N 4-(3-hydroxyphenyl)pyrrolidin-2-one Chemical compound OC1=CC=CC(C2CC(=O)NC2)=C1 DOSDNEYPPVONJR-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- ADJMFKJOMLBOPS-UHFFFAOYSA-N 4-[3-[2-hydroxy-3-(4-phenylpiperazin-1-yl)propoxy]phenyl]pyrrolidin-2-one Chemical compound C1CN(C=2C=CC=CC=2)CCN1CC(O)COC(C=1)=CC=CC=1C1CNC(=O)C1 ADJMFKJOMLBOPS-UHFFFAOYSA-N 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- VZCVJDLXZVVFTB-UHFFFAOYSA-N ClCCOC=1C=C(C=CC1OC)N1C(CCC1)=O Chemical compound ClCCOC=1C=C(C=CC1OC)N1C(CCC1)=O VZCVJDLXZVVFTB-UHFFFAOYSA-N 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- MFESCIUQSIBMSM-UHFFFAOYSA-N I-BCP Chemical compound ClCCCBr MFESCIUQSIBMSM-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- YIPWURPYRDDRFO-UHFFFAOYSA-N [1-[2-methoxy-5-(5-oxopyrrolidin-3-yl)phenoxy]-3-(4-phenylpiperazin-1-yl)propan-2-yl] acetate Chemical compound COC1=CC=C(C2CC(=O)NC2)C=C1OCC(OC(C)=O)CN(CC1)CCN1C1=CC=CC=C1 YIPWURPYRDDRFO-UHFFFAOYSA-N 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 1
- 229910000272 alkali metal oxide Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- ZYBWTEQKHIADDQ-UHFFFAOYSA-N ethanol;methanol Chemical compound OC.CCO ZYBWTEQKHIADDQ-UHFFFAOYSA-N 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000008203 oral pharmaceutical composition Substances 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- 208000019553 vascular disease Diseases 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Cardiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Heart & Thoracic Surgery (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyrrole Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Solid-Sorbent Or Filter-Aiding Compositions (AREA)
- Macromolecular Compounds Obtained By Forming Nitrogen-Containing Linkages In General (AREA)
Description
A találmány tárgya eljárás az I és XVIII. általános képletű új ámino-alkoxi-fenil-pirrolidin-2-onok és sóik előállítására, ahol a képletben m és n jelentése azonos vagy eltérő és 0 vagy 1,The present invention relates to a process according to the invention. for the preparation of novel aminoalkoxyphenylpyrrolidin-2-ones of the formula EMI3.1 wherein m and n are the same or different and are 0 or 1,
Rí jelentése hidrogénatom vagy metoxiesoport,R 1 is hydrogen or methoxy,
R2 jelentése hidrogénatom, egyenes vagy elágazó szénláncú, 1—4 szénatomos alkilcsoport vagy amennyiben m = 1,R 2 is hydrogen, straight or branched C 1 -C 4 alkyl, or when m = 1,
R2 jelentése hidroxilcsoport vagy legfeljebb 6 szénatomos alifás aciloxicsoport,R 2 is hydroxy or aliphatic acyloxy having up to 6 carbon atoms,
R3 jelentése hidrogénatom, egyenes vagy elágazó szénláncú, 1-4 szénatomos alkilcsoport, vagy amennyiben m = 0, hidroxilcsoport, vagy legfeljebb 6 szénatomos alifás aciloxicsoport is lehet ésR 3 is hydrogen, straight or branched C 1 -C 4 alkyl, or when m = 0, hydroxy, or aliphatic acyloxy having up to 6 carbon atoms, and
A jelentése oxigénatom,R5 vagy~CH—Rs általános képletű csoport, amelyben R5 hidrogénatomot, vagy IV, V, VI, VII vagy VIII általános képletű csoportot jelent, amelyekben X jelentése hidrogénatom, halogénatom, trifluor. metilcsoport vagy 1—4 szénatomos alkoxícsoport,A is oxygen, R 5 or -CH-R s group wherein R 5 is hydrogen, or IV, V, VI, VII or VIII group of the formula wherein X is hydrogen, halogen, trifluoromethyl. methyl or C 1-4 alkoxy,
R jelentése pedig IX képletű csoport.R is a group of formula IX.
1—4 szénatomos alkilcsoporton rövidszénláncú alkilcsoportokat kell érteni, így például metil-, etil-, propil-, izopropil-, butil-, izobutil- és terc-butilcsoportot.C 1-4 alkyl is understood to mean lower alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl.
1—6 szénatomos aciloxicsoporton fiziológiailag elviselhető savak savcsoportjait értjük. Előnyös sav például a hangyasav, ecetsav, propionsav, vajsav és kapronsav.C 1-6 acyloxy refers to the acid groups of physiologically tolerable acids. Preferred acids include formic acid, acetic acid, propionic acid, butyric acid and caproic acid.
A találmány szerinti eljárással előállítható vegyületek értágító és vérnyomáscsökkentő hatást mutatnak. Hatékonyságuk az ismert értágítókéhoz képest meglepő módon magasabb.The compounds of the present invention exhibit vasodilator and antihypertensive activity. Surprisingly, their efficiency is higher than that of known vasodilators.
A találmány értelmében úgy állítjuk elő az I és XVIII általános képletű vegyületeket, hogy megfelelő II általános képletű, helyettesített fenil-2-pirrolidonokat — ahol Rí, R2, R3, m és n a fenti jelentésű, és X klóratomot jelent vagy aű-helyzetű szénatommal epoxidgyűrűt alkot - önmagában ismert módon, valamely közömbös oldószerben, szobahőmérséklet feletti hőmérsékleten valamely III általános képletű ciklusos szekunder aminnal, illetve a XVIII általános képletű vegyület előállítása esetén N-(4-nitro-fenil)-piperazinnal kondenzálunk - ahol a képletben A oxigénatomot, ~N RS vagy r=CH—R5 általános képletű csoportot jelent, amelyben R5 hidrogénatomot vagy IV, V, VI, VII vagy VIII általános képletű olyan csoportot jelent, amelyben X hidrogénatomot, halogénatomot vagy trifluormetil- vagy legfeljebb 4 szénatomos alkoxiesoportot képvisel-, és kívánt esetben a szabad hidroxilcsoportot észterezzük és/vagy a kapott, vagy XVIII általános képletű szabad amint a megfelelő sóvá alakítjuk.According to the present invention, the compounds of formula I and XVIII are prepared by reacting the corresponding substituted phenyl-2-pyrrolidones of formula II wherein R 1, R 2 , R 3 , m and n are as defined above and X is chlorine or alpha forms an epoxide ring with carbon atoms, in a manner known per se, in an inert solvent at room temperature, condensed with a cyclic secondary amine of formula III or N- (4-nitrophenyl) piperazine in the preparation of a compound of formula XVIII; ~ NR S, or r = CH-R5 group, wherein R5 is hydrogen, IV, V, VI, VII or VIII or a group of the formula wherein X is hydrogen, halogen or trifluoromethyl, or up to 4 carbon atoms alkoxiesoportot képvisel- and optionally esterifying the free hydroxyl group and / or or the free amine of formula XVIII is converted to the corresponding salt.
A II és III általános képletű vegyületek kondenzálását önmagában ismert módokon valósítjuk meg.The condensation of the compounds of formula II and III is carried out in a manner known per se.
Ha olyan II általános képletű vagyületekből indulunk ki, amelyekben X klóratomot jelent, a III általános képletű szekunder amint kis feleslegben alkalmazzuk valamely bázikus kondenzálószer jelenlétében, valamely közömbös oldószerben.Starting from compounds of formula II in which X represents a chlorine atom, a small excess of the secondary amine of formula III is used in the presence of a basic condensing agent in an inert solvent.
Közömbös oldószerek például az alifás és aromás szénhidrogének, így a ligroin, hexán, benzol és toluol, éterek, így a dietiléter, glikoldimetiléter, tetrahidrofurán és dioxán, alkoholok, így metanol és izopropanol, valamint a halogénezett szénhidrogének, így a kloroform és metilénklorid, valamint a dimetilformamid, dimetilszulf2 axid és hexametilfoszforsavtriamid. Ezeket az oldószereket egymással alkotott elegyeik alakjában is alkalmazhatjuk.Inert solvents include aliphatic and aromatic hydrocarbons such as ligroin, hexane, benzene and toluene, ethers such as diethyl ether, glycol dimethyl ether, tetrahydrofuran and dioxane, alcohols such as methanol and isopropanol, and halogenated hydrocarbons such as chloroform and methylene chloride; dimethylformamide, dimethylsulf2-axide and hexamethylphosphoric triamide. These solvents may also be used in the form of mixtures thereof.
A bázikus kondenzálószer például alkálifém- vagy ilkáliföldfém-hidroxid, így nátrium-, kálium-és kalciumhidroxid, alkálifém- vagy alkáliföldfém-karbonát, így kálium- és magnéziumkarbonát, alkálifémalkoholát, így látriummetilát és kálium-terc-butilát, valamint tercier imin, így trietilamin és tributilamin lehet.Examples of the basic condensing agent include an alkali metal or alkaline earth metal hydroxide such as sodium, potassium and calcium hydroxide, an alkali metal or alkaline earth metal carbonate such as potassium and magnesium carbonate, an alkali metal alcohol such as sodium methylate and butyrate, and tributylamine.
A kondenzálás hőmérséklete szobahőmérséklet feletti, általában 60 °C és 100 °C közötti.The condensation temperature is above room temperature, generally between 60 ° C and 100 ° C.
A reakcióidő egy és nyolc óra közé esik.The reaction time is between one and eight hours.
Ha olyan II általános képletű vegyületekből indulunk ki, amelyekben X a β-helyzetű szénatommal epoxidgyűrűt alkot, a szekunder amint célszerűen csak moláris mennyiségben alkalmazzuk. A bázikus kondenzálószer tt felesleges. A kondenzálást valamely közömbös oldószerben vagy oldószerelegyben végezzük. A reakcióidő és hőmérséklet hasonló a fentiekben leírt kondenzálás esetében megadottal.Starting from compounds of the formula II in which X forms an epoxide ring with the carbon at the β-position, the secondary amine is preferably used only in molar amounts. The basic condensing agent is unnecessary. The condensation is carried out in an inert solvent or solvent mixture. The reaction time and temperature are similar to the condensation described above.
Az olyan II általános képletű kiindulási anyagokat, ímelyekben X a β-helyzetű szénatommal epoxidgyűrűt alkot, ha még nem ismertek, a megfelelő fenolokból állítjuk elő bázikus kondenzálószerek jelenlétében epiklórhidrinnel.Starting materials of the formula II in which X forms an epoxide ring with the β-carbon atom, if not already known, are prepared from the corresponding phenols in the presence of basic condensing agents with epichlorohydrin.
Az olyan II általános képletű kiindulási anyagokat, amelyekben X klóratomot jelent, ha még nem ismertek, a fentiekben megnevezett epoxidokból állítjuk elő sósavval végzett reagáltatással. Előállíthatjuk őket azonban közvetlenül is oly módon, hogy a megfelelő fenolokat katalitikus mennyiségű bázis, például piperidin jelenlétében epiklórhidrinnel reagáltatjuk.The starting materials of the formula II in which X represents a chlorine atom, if not already known, are prepared from the above-mentioned epoxides by reaction with hydrochloric acid. However, they can also be prepared directly by reacting the corresponding phenols with epichlorohydrin in the presence of a catalytic amount of a base such as piperidine.
Valamely szabad hidroxilcsoport kívánt esetben megvalósított ezt követő észterezését szintén önmagában ismert módon végezzük. Előnyösen úgy járunk el, hogy a reagáltatást valamely reakcióképes savszármazékkal végezzük valamely bázikus katalizátor jelenlétében, így például valamely savkloriddal vagy savanhidriddel piridin jelenlétében.Subsequent optional esterification of a free hydroxyl group is also carried out in a manner known per se. Preferably, the reaction is conducted with a reactive acid derivative in the presence of a basic catalyst such as an acid chloride or anhydride in the presence of pyridine.
A szabad amin sóvá alakítását szintén önmagában ismert módon valósítjuk meg. Ekkor az amint a kívánt savval híg oldatból kicsapjuk. Előnyösek a sósawal képzett sók, ekkor hidrokloridok képződnek.Conversion of the free amine to the salt is also accomplished in a manner known per se. The amine is then precipitated from the dilute solution with the desired acid. Salts with hydrochloric acid are preferred, whereby hydrochlorides are formed.
A találmány szerinti eljárással előállítható I általános képletű vegyületeket gyógyászati készítmények hatóanyagaként alkalmazhatjuk. Ezek a gyógyászati készítmények érrendszeri megbetegedések és magas vérnyomás kezelésére használhatók a humán terápiában.The compounds of formula I which are obtainable by the process of the present invention can be used as active ingredients in pharmaceutical compositions. These pharmaceutical compositions are useful in the treatment of vascular diseases and hypertension in human therapy.
Néhány, találmány szerinti eljárással előállítható vegyület vérnyomáscsökkentő hatását (ED40) az alábbi táblázatban foglaljuk össze, összehasonlító anyagként a 2 263 211 számú német szövetségi köztársaságbeli közzétételi iratban szereplő, XXVII képletű vegyületet használtuk.The antihypertensive activity (ED40) of some of the compounds of the present invention is summarized in the following table, using the compound of Formula XXVII in German Patent Publication No. 2,263,211.
Vérnyomáscsökkentő hatás (ED40)Antihypertensive effect (ED 40 )
Vegyület képletszáma Előállítási példa ED^ vagy kémiai neve számaCompound Formula Number Production Example ED ^ or chemical name number
XXVII 0,62XXVII 0.62
4- {3-[2-hidroxi-3-(4-fenil-piperazin-1 -il)-propoxi]-fenil} -2-pirro-. lidon 4. 0,284- {3- [2-Hydroxy-3- (4-phenyl-piperazin-1-yl) -propoxy] -phenyl} -2-pyrrole. lidon 4. 0.28
-2183 103-2183 103
Vegyület képletszáma Előállítási példa ED^oCompound Formula Example Preparation ED ^ p
Terápiás célra a találmány szerinti eljárással előállítható I általános képletű vegyületeket orálisan adagoljuk 35 napi 0,1-500 mg, előnyösen 1 —50 mg adagban.For therapeutic purposes, the compounds of formula I, which are obtainable by the method of the invention, are administered orally in a daily dose of 0.1 to 500 mg, preferably 1 to 50 mg, per day.
Az orálisan beadható gyógyászati készítmények 0,05—, körülbelül 500 mg, előnyösen körülbelül 0,1 — körülbelül 25 mg hatóanyagot tartalmaznak adagolási egységenként. 40Oral pharmaceutical compositions contain from 0.05 to about 500 mg, preferably from about 0.1 to about 25 mg, of active ingredient per unit dosage form. 40
Gyógyászati készítményként történő beadás céljára a hatóanyagokból egyebek között tablettát, granulátumot, port, kapszulát készíthetünk. A hatóanyagot általában segédanyagokkal vagy hordozóanyagokkal együtt adagoljuk, így például laktózzal, magnéziumsztearáttal, 45 kaolinnal, szacharózzal, kukoricakeményítővel, talkummal, sztearinsavval, zselatinnal, agar-agarral, pektinnel stb.For administration as a pharmaceutical preparation, the active compounds may be formulated, inter alia, in the form of tablets, granules, powders, capsules. The active ingredient is usually administered in admixture with excipients or carriers such as lactose, magnesium stearate, kaolin 45, sucrose, corn starch, talc, stearic acid, gelatin, agar, pectin and the like.
A találmány szerinti eljárást közelebbről az alábbi példáikkal szemléltetjük.The invention is further illustrated by the following examples.
A nyersterméknek nevezett anyagok kielégítő tisztaságát vékonyrétegkromatográfiásan legalább két rendszerben és infravörös spektrum segítségével vizsgáltuk. Az összes többi anyag analitikai tisztaságú (elementár analízis, IR-, UV- és MMR-spektrum, vékonyrétegkromatogramm).The satisfactory purity of the raw material was investigated by thin layer chromatography in at least two systems and by infrared spectra. All other materials are of analytical purity (elemental analysis, IR, UV and MMR, TLC).
Az olvadáspontokat Kofler-készüléken határoztuk meg. Az átkristályosításhoz használt oldószert az olvadáspont után zárójelben adjuk meg.Melting points were determined on a Kofler apparatus. The solvent used for recrystallization is given in brackets after the melting point.
1. példaExample 1
15,5 mmól 4-[3-(2,3-epoxi-propoxi)-4-metoxi-fenil]-2-pirrolidont 50 ml metanolban feloldunk. Hozzáadunk15.5 mmol of 4- [3- (2,3-epoxypropoxy) -4-methoxyphenyl] -2-pyrrolidone are dissolved in 50 ml of methanol. added
15,5 mmól 95 %-os 1-fenilpiperazint, és az elegyet 3 órán át forraljuk visszafolyató hűtő alkalmazásával. A reakcióelegy lehűlése után az oldószert vákuumban, 40 °C hőmérsékleten ledesztilláljuk. A maradékot 50 ml n sósav-oldatban felvesszük, és két alkalommal, 100— 100 ml kloroformmal extraháljuk. A vizes fázist 2 n nátriumhidroxid-oldattal meglúgosítjuk, majd etilacetáttal háromszor extraháljuk. Az egyesített etilacetátos fázisokat telített nátriumklorid-oldattal mossuk, és az oldószert nátriumszulfát fölött végzett szárítás után vákuumban ledesztilláljuk. A maradékot etanolból átkristályositjuk. Ily módon 4-{4-metoxi-3-[3-(4-fenil-piperazin-l-i!)-2-hidroxi-propoxi]-fenil} -2-pirrolidont kapunk, anelynek olvadáspontja 143—144 °C; kitermelés: 61 %.15.5 mmol of 95% 1-phenylpiperazine and the mixture was refluxed for 3 hours. After cooling, the solvent was evaporated in vacuo at 40 ° C. The residue was taken up in 50 ml of n hydrochloric acid and extracted twice with 100 ml of chloroform each. The aqueous phase was made basic with 2N sodium hydroxide solution and extracted three times with ethyl acetate. The combined ethyl acetate phases were washed with saturated sodium chloride solution and the solvent was evaporated in vacuo after drying over sodium sulfate. The residue was recrystallized from ethanol. 4- {4-Methoxy-3- [3- (4-phenyl-piperazin-1-yl) -2-hydroxy-propoxy] -phenyl} -2-pyrrolidone is obtained, m.p. 143-144 ° C; yield: 61%.
Éteres sósav-oldattal lecsapjuk a dihidrokloridot, anelynek olvadáspontja 167—169 °C.The dihydrochloride was precipitated with ethereal hydrochloric acid, m.p. 167-169 ° C.
A kiindulási anyagként használt 4-[3-(2,3-epoxi-propoxi)-4-metoxi-fenil]-2 -pirrolidont (olvadáspont: 124— 126 °C) 4-(3-hidroxi-4-metoxi-fenil)-2-pirrolidon, epiklórhidrin és nátriumhidrid dimetilformamidban való reagáltatásával állítjuk elő.4- [3- (2,3-epoxypropoxy) -4-methoxyphenyl] -2-pyrrolidone (m.p. 124-126 ° C), starting from 4- (3-hydroxy-4-methoxyphenyl) ) By reaction of -2-pyrrolidone, epichlorohydrin and sodium hydride in dimethylformamide.
2. példaExample 2
Az 1. példa szerinti módon eljárva állítjuk elő 4-[3-i 2,3-epoxi-propoxi)4-metoxi-fenil]-2-pirrolidonból és s megfelelő szekunder aminból az alábbi táblázatban szereplő vegyületeket, ahol R IX képletű csoportot j :lent.By following the procedure of Example 1, the following compounds were prepared from 4- [3- (2,3-epoxypropoxy) -4-methoxyphenyl] -2-pyrrolidone and the corresponding secondary amine, wherein R :below.
-3183 103-3183 103
3. példaExample 3
6. példaExample 6
11,5 mmól 4-(4-(2,3-epoxi-propoxi)-3-metoxi-fenil)-2-pirrolidonból és 11,5 mmól 95 %-os 1-fenil-piperazinból az 1. példa szerinti módon eljárva 74 %-os kitermeléssel kapjuk a 4-{ 3-metoxi-4-[3-(4-fenil-piperazin-l-il)-2-hidroxi-propoxi]-fenil} -2-pirTolidont, amelynek olvadáspontja 123-125 °C (etanol; metanol és kloroform 1:1 arányú elegyéből végzett kromatografálás után).11.5 mmol of 4- (4- (2,3-epoxypropoxy) -3-methoxyphenyl) -2-pyrrolidone and 11.5 mmol of 95% 1-phenylpiperazine according to the procedure of Example 1. 74% yield of 4- {3-methoxy-4- [3- (4-phenylpiperazin-1-yl) -2-hydroxypropoxy] phenyl} -2-pyrrolidone, m.p. 123-125. ° C (after ethanol; 1: 1 methanol: chloroform).
A kiindulási anyagként használt 4-(4-(2,3-epoxi-propoxi)-3-metoxi-fenil]-2-pirrolidont (olvadáspont: 108110 9C) 4-(4-hidroxi-3-metoxi-fenil)-2-pirrolidon, epiklórhidrin és nátriumhidrid dimetilformamidban végzett reagáltatásával állítjuk elő.The starting material, 4- (4- (2,3-epoxypropoxy) -3-methoxyphenyl] -2-pyrrolidone (m.p. 108 110 C 9) 4- (4-hydroxy-3-methoxyphenyl) - It is prepared by reacting 2-pyrrolidone, epichlorohydrin and sodium hydride in dimethylformamide.
4. példaExample 4
8,6 mmól 4-(3-(2,3-epoxi-propoxi)-fenil]-2-pirrolidonból és 8,6 mmól 95 %-os 1-fenil-piperazinból az 1. példa szerinti módon eljárva 77 %-os kitermeléssel kapjuk a 4- {3-[2-hidroxi-3-(4-fenil-piperazin-l-il)-propoxi]-fenil } -2-pirrolidont, amelynek olvadáspontja 82—84 °C (éter; metanol és kloroform 2:8 arányú elegyéből végzett kromatografálás után).Of 4- (3- (2,3-epoxypropoxy) phenyl] -2-pyrrolidone (8.6 mmol) and 95% 1-phenylpiperazine (95%) were treated as in Example 1 with Yield: 4- {3- [2-hydroxy-3- (4-phenylpiperazin-1-yl) -propoxy] -phenyl} -2-pyrrolidone, m.p. 82-84 ° C (ether; methanol and chloroform). 2: 8).
A kiindulási anyagként használt 4-(3-(2,3-epoxi-propoxi)-fenil]-2-pirrolidont (olajszerű anyag) 4-(3-hidroxi-fenil)-2-pirrolidon, epiklórhidrin és nátriumhidrid dimetilformamidban végzett reagáltatásával állítjuk elő.The starting material 4- (3- (2,3-epoxypropoxy) phenyl] -2-pyrrolidone (oily substance) is obtained by reacting 4- (3-hydroxyphenyl) -2-pyrrolidone, epichlorohydrin and sodium hydride in dimethylformamide. live.
5. példa mmól 5-[3-(2,3-epoxi-propoxi)4-metoxi-fenil]-2-pirrolidonból és 10 mmól 95 %-os 1-fenil-piperazinból 52 %-os kitermeléssel állítjuk elő az 5-{3-[2-hidroxi-3-(4-fenil-piperazin-l-il)-propoxi]-4-metoxi-fenil} -2-pirrolidont, amelynek olvadáspontja 127-131 °C (etanol).EXAMPLE 5 5- [3- (2,3-Epoxy-propoxy) -4-methoxy-phenyl] -2-pyrrolidone and 10 mmol of 95% 1-phenyl-piperazine in 52% yield were prepared. {3- [2-Hydroxy-3- (4-phenyl-piperazin-1-yl) -propoxy] -4-methoxy-phenyl} -2-pyrrolidone, m.p. 127-131 ° C (ethanol).
A kiindulási anyagként használt 5-(3-(2,3-epoxi-propoxi)-4-metoxi-fenil]-2-pirrolidont (olvadáspont: 140— 142 °C) 5-(3-hidroxi4-metoxi-fenil]-2-pirrolidon, epiklórhidrin és nátriumhidrid dimetilformamidban végzett reagáltatásával állítjuk elő.Starting material 5- (3- (2,3-epoxypropoxy) -4-methoxyphenyl] -2-pyrrolidone (m.p. 140-142 ° C) 5- (3-hydroxy-4-methoxyphenyl) - It is prepared by reacting 2-pyrrolidone, epichlorohydrin and sodium hydride in dimethylformamide.
mmól 3-(3-(2,3-epoxi-propoxi)4-metoxi-fenil]-2-pirrolidonból és 10 mmól 95 %-os 1-fenil-piperazinból 5 60 %-os kitermeléssel állítjuk elő a 3-{3-[2-hidroxi-3-i 4-fenil-piperazin-l -il)-propoxi]4-metöxi-fenil} -2-pirrolidont, amelynek olvadáspontja 146-147 °C.3- (3- (2,3-epoxypropoxy) 4-methoxyphenyl] -2-pyrrolidone and 10 mmol 95% 1-phenylpiperazine (5 mmol) were prepared in 60% yield from 3- {3 - [2-Hydroxy-3-yl-4-phenyl-piperazin-1-yl] -propoxy] -4-methoxy-phenyl} -2-pyrrolidone, m.p. 146-147 ° C.
A kiindulási anyagként alkalmazott 3-(3-(2,3-epoxi-propoxi)4-metoxi-fenil]-2-pirrolidont (olvadáspont: 1(j 110-112 °C) 3-(3-hidroxi4-metoxi-fenil)-2-pirrolidin, epiklórhidrin és nátriumhidrid dimetilformamidban végzett reagáltatásával állítjuk elő.3- (3- (2,3-epoxypropoxy) 4-methoxyphenyl) -2-pyrrolidone (m.p. 1 ( 110-112 ° C)) 3- (3-hydroxy-4-methoxyphenyl) was used as starting material. ) By reaction of -2-pyrrolidine, epichlorohydrin and sodium hydride in dimethylformamide.
7. példaExample 7
20 mmól 4-[3-(2-klór-etoxi)4-metoxi-fenil]-2-pirrolidont 50 ml dimetil-formamidban féloldunk. 22 mmól 95 %-os 1-fenil-piperazin és 20 mmól trietil-amin beadagolása után a reakcióelegyet 6 órán át melegítjük 100 °C hőmérsékleten. A reagáltatás befejezése után az oldó25 szert 40 °C hőmérsékleten, na® vákuumban ledesztilláljuk. A maradékot 50 ml etil-acetátban felvesszük, félig elitett nátriumklorid-oldattal mossuk, és az oldószert nátriumszulfát felett végzett szárítás után vákuumban ledesztilláljuk. Ily módon 4-{ 4-metoxi-3-[2-(4-fenil-piperazin-l-il)-etoxi]-fenil} -2-pirrolidont kapunk 15,2%-os kitermeléssel: olvadáspont: 140-141 °C.4- [3- (2-Chloroethoxy) 4-methoxyphenyl] -2-pyrrolidone (20 mmol) was dissolved in 50 mL of dimethylformamide. After addition of 22 mmol of 95% 1-phenylpiperazine and 20 mmol of triethylamine, the reaction mixture was heated at 100 ° C for 6 hours. After completion of the reaction, the solvent is distilled off at 40 ° C in vacuo. The residue is taken up in 50 ml of ethyl acetate, washed with half-saturated sodium chloride solution and the solvent is evaporated in vacuo after drying over sodium sulphate. 4- {4-Methoxy-3- [2- (4-phenyl-piperazin-1-yl) -ethoxy] -phenyl} -2-pyrrolidone was obtained in 15.2% yield, m.p. 140-141 ° C. C.
Éteres sósav-oldatból kicsapjuk a dihidrokloridot, olvadáspontja 219—221 °C.The dihydrochloride was precipitated from ethereal hydrochloric acid, m.p. 219-221 ° C.
A kiindulási anyagként használt 4-[3-(2-klór-etoxi)4metoxi-fenil]-2-pirrolidont (olvadáspont: 134-138 °C) l-bróm-2-klór-etán, 4-(3-hidroxi-4-metoxi-fenil)-2-pirro’idon és nátriumhidrid dimetilformamidban végzett reagáltatásával· állítjuk elő.The starting material was 4- [3- (2-chloroethoxy) 4-methoxyphenyl] -2-pyrrolidone (m.p. 134-138 ° C), 1-bromo-2-chloroethane, 4- (3-hydroxy) By reaction of 4-methoxyphenyl) -2-pyrrolidone with sodium hydride in dimethylformamide.
A fenti példában leírt módon eljárva állítjuk elő l-[3-(2-klór-etoxi)4-metoxi-fenil]-2-pirrolidonból és a megfelelő szekunder aminból az alábbi táblázatban felsorolt ve®ületeket, ahol R' XXII képletű csoportot jelent.By following the procedure described above, the following compounds are prepared from 1- [3- (2-chloroethoxy) 4-methoxyphenyl] -2-pyrrolidone and the corresponding secondary amine, wherein R 'is a group of formula XXII. .
DMF = dimetil-formamidDMF = dimethylformamide
183 103183 103
8. példa mmól 4-[3-(3-klór-propoxi)-4-metoxi-fenil]-2-pirrolidonból és 5,5 mmól 95 %-os 1-fenil-piperazinból aExample 8 From 4- [3- (3-chloropropoxy) -4-methoxyphenyl] -2-pyrrolidone and 5.5 mmol 95% 1-phenylpiperazine
7. példa szerinti módon eljárva 22,5 %-os kitermeléssel állítjuk elő a 4-(4-metoxi-3-[3-(4-fenil-piperazin-l-il)-propoxi]-fenil} -2-pirrolidont, amelynek olvadáspontja 135-137 °C (etanol).In a similar manner to Example 7, 4- (4-methoxy-3- [3- (4-phenyl-piperazin-1-yl) -propoxy] -phenyl) -2-pyrrolidone was obtained in 22.5% yield, m.p. 135-137 ° C (ethanol).
A kiindulási anyagként használt 4-[3-(3-klór-propoxi)-4-metoxi-fenil]-2-pirrolidont (olvadáspont: 128-130°C) 4-(3-hidroxi-4-metoxi-fenil)-2-pirrolidon, 1-bróm-3-klór-propán és nátriumhidrid dimetilformamidban végzett reagáltatásával állítjuk elő.4- [3- (3-chloropropoxy) -4-methoxyphenyl] -2-pyrrolidone (m.p. 128-130 ° C), starting material 4- (3-hydroxy-4-methoxyphenyl) - It is prepared by reacting 2-pyrrolidone, 1-bromo-3-chloropropane and sodium hydride in dimethylformamide.
9. példa mmól 4-[3-(3-klór-propoxí)-4-metoxi-fenil]-2-pirrolidonból és 11 mmól 4-(4-fluor-benzoil)-piperidinből a 7. példa szerinti módon eljárva 23 %-os kitermeléssel állítjuk elő a 4- { { 4-metoxi-3- { 3-[4-(4-fluor-benzoil)-píperidin-l-il]-propoxi}-fenil}} -2-pirrolidont, amelynek olvadáspontja 104—105 °C (etanol; metanol és kloroform 9:1 arányú elegyéből végzett kromatografálás után).Example 9 From 4- [3- (3-chloropropoxy) -4-methoxyphenyl] -2-pyrrolidone and 11 mmol 4- (4-fluorobenzoyl) -piperidine, 23% 4- {{4-methoxy-3- {3- [4- (4-fluorobenzoyl) -piperidin-1-yl] -propoxy} -phenyl}} -2-pyrrolidone, m.p. 104-105 ° C (after chromatography on ethanol; methanol: chloroform = 9: 1).
10. példa mmól 4-[3-(4-bróm-butoxi)-4-metoxi-fenil]-2-pirrolidonból és 22 mmól 95 %-os 1-fenil-piperazinból 30 %-os kitermeléssel állítjuk elő a 4-{ 4-metoxi-3-[4-(4-fenil-piperazin-l-il)-butoxi]-fenil} -2-pirrolidont, amelynek olvadáspontja 123-124 °C (etil-acetát).Example 10 4- [3- (4-Bromobutoxy) -4-methoxyphenyl] -2-pyrrolidone and 22 mmol 95% 1-phenylpiperazine (22 mmol) were prepared in 30% yield. 4-methoxy-3- [4- (4-phenylpiperazin-1-yl) butoxy] phenyl} -2-pyrrolidone, m.p. 123-124 ° C (ethyl acetate).
A kiindulási anyagként használt 4-[3-(4-bróm-butoxi)-4-metoxi-fenil]-2-pirrolidont (olvadáspont:116-119 C) 4-(3-hidroxi4-metoxi-fenil)-2-pirrolidon, 1,4-dibróm-bután és nátriumhidrid dimetil-formamidban végzett reagáltatásával állítjuk elő.4- [3- (4-Bromobutoxy) -4-methoxyphenyl] -2-pyrrolidone (m.p. 116-119 ° C) 4- (3-hydroxy-4-methoxyphenyl) -2-pyrrolidone was used as starting material. , 1,4-dibromobutane and sodium hydride in dimethylformamide.
11. példa tExample 11 t
7,5 mmól 4- {4-metoxi-3-[3-(4-fenil-piperazin-l-il)-2-hidroxí-propoxij-fenil} -2-pirrolidont 50 ml száraz piridinben feloldunk. 15 mmól ecetsavanhidrid beadagolása után a reakcióelegyet 3 órán át forraljuk visszafolyató hűtő alkalmazásával. Lehűlés után a reakcióelegyet vákuumban bepároljuk. A maradékot kovasavgélen kromatografáljuk (aceton és diklórmetán 1:1 arányú elegye), és izopropanolból átkristályosítjuk. Ily módon 4-{4-metoxi -3 - [3 -(4-fenil-piperazin-1 -il) - 2-acetoxi-propoxi] -fenil }-2-pirrolidont kapunk 86 %-os kitermeléssel; olvadáspont: 128—133 °C.7.5 mmol of 4- {4-methoxy-3- [3- (4-phenylpiperazin-1-yl) -2-hydroxypropoxy] phenyl} -2-pyrrolidone is dissolved in 50 ml of dry pyridine. After addition of 15 mmol acetic anhydride, the reaction mixture was refluxed for 3 hours. After cooling, the reaction mixture was concentrated in vacuo. The residue was chromatographed on silica gel (acetone: dichloromethane = 1: 1) and recrystallized from isopropanol. 4- {4-methoxy-3- [3- (4-phenyl-piperazin-1-yl) -2-acetoxy-propoxy] -phenyl} -2-pyrrolidone was obtained in 86% yield; 128-133 ° C.
12. példa mmól 4-[3-(l-metil-2,3-epoxi-propoxi)-4-metoxi-fenil]-2-pirrolidonból és 10 mmól 95 %-os 1-fenil-piperazinból az 1. példa szerinti módon eljárva 68 %-os kitermeléssel állítjuk elő a 4-{4-metoxi-3-[3-(4-fenil-piperazin-1 -il)-l-metil-2-hidroxi-propoxiJ-fenil}-2-pirrolidont, amelynek olvadáspont)a 116-118 C(etanol).Example 12 4- [3- (1-Methyl-2,3-epoxy-propoxy) -4-methoxy-phenyl] -2-pyrrolidone and 10 mmol of 95% 1-phenyl-piperazine in Example 1 4- (4-Methoxy-3- [3- (4-phenyl-piperazin-1-yl) -1-methyl-2-hydroxy-propoxy] -phenyl) -2-pyrrolidone was obtained in 68% yield. m.p. 116-118 ° C (ethanol).
A kiindulási anyagként használt 4-[3-(l-metil-2,3-epoxi-propoxi)-4-metoxi-fenil]-2-pirrolidont (olvadáspont: 121-125 °C) 4-(3-hidroxi4-metoxi-fenil)-2-pirroliion, 3-bróm-l,2-epoxi-bután (amelyet Santelli, M. módszere szerint állítottunk elő: THL, 1977., 50., 4397. oídal) és nátriumhidrid dimetil-formamidban végzett reagáltatásával állítjuk elő.4- [3- (1-methyl-2,3-epoxypropoxy) -4-methoxyphenyl] -2-pyrrolidone (m.p. 121-125 ° C), starting from 4- (3-hydroxy-4-methoxy) -phenyl) -2-pyrrolionone, by reaction of 3-bromo-1,2-epoxybutane (prepared by Santelli, M.M., 1977, pp. 50, 4397) and sodium hydride in dimethylformamide. live.
13. példa mmól 4-[3-(3-bróm-butoxi)-4-metoxi-fenil]-2-pirrolidonból és 11 mmól 95 %-os 1-fenil-piperazinból a 7. példa szerinti módon eljárva 19,8 %-os kitermeléssel állítjuk elő a 4-{4-metoxi-3-[3-metil-3-(4-fenil-piperazín-i-il)-propoxi]-fenil}-2-pirrolidont, amelynek olvadáspontja 88-90 °C (etanol; metanol és kloroform 1:9 arányú elegyéből végzett kromatografálás után).Example 13 From 4- [3- (3-bromobutoxy) -4-methoxyphenyl] -2-pyrrolidone and 11 mmol 95% 1-phenylpiperazine from Example 7 19.8% 4- {4-methoxy-3- [3-methyl-3- (4-phenyl-piperazin-1-yl) -propoxy] -phenyl} -2-pyrrolidone, m.p. 88-90 ° C. C (ethanol; after chromatography on methanol: chloroform = 1: 9).
Éteres sósav-oldatból csapjuk le a dihidrokloridot, a melynek olvadáspontja 120 C (bomlás).The dihydrochloride was precipitated from ethereal hydrochloric acid with a melting point of 120 DEG C. (decomposition).
A kiindulási anyagként használt 4-[3-(3-bróm-butoxi)4-metoxi-fenil]-2-pirrolidont (olajszerű anyag) 1,3-ditróm-bután, 4-(3-hidroxi-4-metoxi-fenil)-2-pirrolidon és nátriumhidrid dimetil-formamidban végzett reagáltatásáral állítjuk elő.The starting material used is 4- [3- (3-bromobutoxy) 4-methoxyphenyl] -2-pyrrolidone (oily substance), 1,3-nitrobutane, 4- (3-hydroxy-4-methoxyphenyl). ) By reaction of -2-pyrrolidone and sodium hydride in dimethylformamide.
14. példa mmól 3-[3-(2-klór-etoxi)-4-metoxi-fenil]-2-pirrolidonból, 11,5 mmól (95 %-os) 1-fenil-piperazinból és 0 mmól trietil-aminból állítjuk elő a 7. példában leírt módon 43 %-os kitermeléssel a 3-(4-metoxi-3-[2-(4-fenil-piperazin-l-il)-etoxi]-fenil} -2-pirrolidont, amelynek olvadáspontja etilacetátból való átkristályosítás után 104—106°C.Example 14 Prepared from 3- [3- (2-chloroethoxy) -4-methoxyphenyl] -2-pyrrolidone, 11.5 mmol (95%) 1-phenylpiperazine and 0 mmol triethylamine 3- (4-Methoxy-3- [2- (4-phenyl-piperazin-1-yl) -ethoxy] -phenyl) -2-pyrrolidone, m.p. 104-106 ° C.
A kiindulási anyagként alkalmazott 3-[3-(2-klóretoxi)-4-metoxi-fenil]-2-pirrolidont (olajszerű anyag) így állítjuk elő, hogy 1 -bróm-2-klór-etánt dimetilformanidban 3-(3-hídroxi-4-metoxi-fenil)-2-pirrolidinnel és tátriumhidriddel reagáltatunk.The starting material 3- [3- (2-chloroethoxy) -4-methoxyphenyl] -2-pyrrolidone (oily substance) was prepared by treating 3- (3-hydroxy) 1-bromo-2-chloroethane with dimethylforman -4-methoxyphenyl) -2-pyrrolidine and sodium hydride.
Claims (25)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19782834114 DE2834114A1 (en) | 1978-08-01 | 1978-08-01 | POLYALKOXYPHENYLPYRROLIDONE III, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| HU183103B true HU183103B (en) | 1984-04-28 |
Family
ID=6046151
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| HU79SCHE685A HU183103B (en) | 1978-08-01 | 1979-07-31 | Process for producing amino-alkoxy-pyrrolidin-2-ones |
Country Status (15)
| Country | Link |
|---|---|
| US (1) | US4219551A (en) |
| EP (1) | EP0008645B1 (en) |
| JP (1) | JPS5522686A (en) |
| AT (1) | ATE9221T1 (en) |
| AU (1) | AU533442B2 (en) |
| CA (1) | CA1115701A (en) |
| CS (1) | CS225816B2 (en) |
| DD (1) | DD145104B3 (en) |
| DE (2) | DE2834114A1 (en) |
| DK (1) | DK152426C (en) |
| ES (1) | ES482917A1 (en) |
| HU (1) | HU183103B (en) |
| IE (1) | IE48915B1 (en) |
| IL (1) | IL57926A (en) |
| SU (1) | SU878197A3 (en) |
Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3424685A1 (en) * | 1984-07-05 | 1986-02-06 | Beiersdorf Ag, 2000 Hamburg | NEW SUBSTITUTED PHENYLPIPERAZINYL PROPANOLS, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE, AND PREPARATIONS CONTAINING THESE COMPOUNDS |
| SE8500573D0 (en) * | 1985-02-08 | 1985-02-08 | Ferrosan Ab | NOVEL PIPERAZINECARBOXAMIDES HAVING A PHENOXYALKYL OR THIOPHENOXYALKYL SIDE CHAIN |
| WO1988003136A1 (en) * | 1986-10-27 | 1988-05-05 | Yoshitomi Pharmaceutical Industries, Ltd. | Piperazine compounds and their medicinal use |
| DE3809031A1 (en) * | 1988-03-15 | 1989-09-28 | Schering Ag | NEW AGENT AGAINST OBSTRUCTIVE BLADDER EMPTYING |
| DE3921593A1 (en) * | 1989-06-28 | 1991-01-10 | Schering Ag | METHOD FOR THE RACEMATE SEPARATION OF 4-ARYL-2-OXO-PYRROLIDIN-3-CARBONIC ACID ESTER |
| DE19648011A1 (en) * | 1996-11-20 | 1998-05-28 | Bayer Ag | Cyclic imines |
| CA2454059A1 (en) * | 2001-07-19 | 2003-01-30 | Cv Therapeutics, Inc. | Substituted piperazine compounds and their use as fatty acid oxidation inhibitors |
| DE60233884D1 (en) * | 2001-10-16 | 2009-11-12 | Memory Pharmaceutical Corp | 4 (4-ALKOXY-3-HYDROXYPHENYL) -2-PYRROLIDONE DERIVATIVES AS PDE-4 INHIBITORS FOR THE TREATMENT OF NEUROLOGICAL SYNDROMES |
| CA2522631A1 (en) * | 2003-04-16 | 2004-11-04 | Memory Pharmaceuticals Corporation | 4 - (3,4 - disubstituted phenyl) - pyrrolidin-2-one compounds as phosphodiesterase 4 inhibitors |
| US7226930B2 (en) * | 2003-04-18 | 2007-06-05 | Memory Pharmaceutical Corporation | Phosphodiesterase 4 inhibitors |
| EP1799673A1 (en) | 2004-10-15 | 2007-06-27 | Memory Pharmaceuticals Corporation | Pyrazole derivatives as phosphodiesterase 4 inhibitors |
| EP1802615A1 (en) * | 2004-10-20 | 2007-07-04 | Memory Pharmaceuticals Corporation | Phosphodiesterase 4 inhibitors |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3577415A (en) * | 1968-12-23 | 1971-05-04 | Robins Co Inc A H | 1-substituted-3-substituted phenoxypyrrolidines |
| DE2263211A1 (en) * | 1972-12-23 | 1974-07-04 | Boehringer Sohn Ingelheim | NEW ARYLPIPERAZINE AND PROCESS FOR THEIR PRODUCTION |
| DE2337461A1 (en) * | 1973-07-24 | 1975-02-06 | Boehringer Mannheim Gmbh | NEW INDOLDER DERIVATIVES AND PROCESS FOR THEIR PRODUCTION |
| US4120969A (en) * | 1975-09-23 | 1978-10-17 | A. H. Robins Company, Incorporated | Heterocyclic analgetic and antidiarrheal compounds |
| DE2737630A1 (en) * | 1977-08-20 | 1979-03-01 | Boehringer Mannheim Gmbh | 3-Phenoxymethyl-piperidino 1-heterocyclyl-oxo-propane derivs. - useful as vasodilators and beta adrenergic receptor inhibitors |
| US4096331A (en) * | 1976-12-28 | 1978-06-20 | A. H. Robins Company, Incorporated | 1-Substituted-3-aminoethoxypyrrolidines |
-
1978
- 1978-08-01 DE DE19782834114 patent/DE2834114A1/en not_active Withdrawn
-
1979
- 1979-07-18 EP EP79102507A patent/EP0008645B1/en not_active Expired
- 1979-07-18 AT AT79102507T patent/ATE9221T1/en not_active IP Right Cessation
- 1979-07-18 DE DE7979102507T patent/DE2967204D1/en not_active Expired
- 1979-07-27 DD DD79214657A patent/DD145104B3/en unknown
- 1979-07-27 ES ES482917A patent/ES482917A1/en not_active Expired
- 1979-07-31 DK DK323179A patent/DK152426C/en not_active IP Right Cessation
- 1979-07-31 HU HU79SCHE685A patent/HU183103B/en not_active IP Right Cessation
- 1979-07-31 IL IL57926A patent/IL57926A/en unknown
- 1979-07-31 CA CA332,897A patent/CA1115701A/en not_active Expired
- 1979-07-31 SU SU792791951A patent/SU878197A3/en active
- 1979-08-01 CS CS795308A patent/CS225816B2/en unknown
- 1979-08-01 AU AU49440/79A patent/AU533442B2/en not_active Ceased
- 1979-08-01 US US06/062,865 patent/US4219551A/en not_active Expired - Lifetime
- 1979-08-01 JP JP9742379A patent/JPS5522686A/en active Granted
- 1979-08-08 IE IE1453/79A patent/IE48915B1/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| AU4944079A (en) | 1980-02-07 |
| DE2967204D1 (en) | 1984-10-11 |
| JPH0371423B2 (en) | 1991-11-13 |
| IL57926A0 (en) | 1979-11-30 |
| EP0008645A1 (en) | 1980-03-19 |
| DD145104B3 (en) | 1990-07-18 |
| US4219551A (en) | 1980-08-26 |
| CS225816B2 (en) | 1984-02-13 |
| ATE9221T1 (en) | 1984-09-15 |
| DD145104A5 (en) | 1980-11-19 |
| ES482917A1 (en) | 1980-04-16 |
| DE2834114A1 (en) | 1980-02-14 |
| EP0008645B1 (en) | 1984-09-05 |
| IE48915B1 (en) | 1985-06-12 |
| DK152426B (en) | 1988-02-29 |
| JPS5522686A (en) | 1980-02-18 |
| CA1115701A (en) | 1982-01-05 |
| SU878197A3 (en) | 1981-10-30 |
| IL57926A (en) | 1983-10-31 |
| DK323179A (en) | 1980-02-02 |
| DK152426C (en) | 1988-08-29 |
| AU533442B2 (en) | 1983-11-24 |
| IE791453L (en) | 1980-02-01 |
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| HU90 | Patent valid on 900628 | ||
| HMM4 | Cancellation of final prot. due to non-payment of fee |